Search Results (269)

SYNGAP1-related disorder is a rare neurodevelopmental disorder characterized by intellectual and motor disabilities, including disordered gait control. Currently, there have been few studies that have assessed the gait of individuals with SYNGAP1-related disorder using technology-based collection techniques. The purpose of this investigation was to characterize the kinematic gait pattern of these individuals using camera-based motion capture technology during treadmill walking. Both linear and non-linear analysis techniques were used to analyze bilateral lower-limb joint motion and compare the results to age-matched neurotypical individuals. Results indicate that joint range of motion and velocity were decreased in the patient population relative to the neurotypical participants with the non-linear measures of angle–angle and phase portrait areas reflecting similar outcomes. The combination of linear and non-linear measures provide complementary information that, when used in combination, can provide deeper insights into the coordination and control of gait than if either of the measurement techniques are used in isolation. Such information can be useful to clinicians and therapists to develop targeted interventions designed to improve the gait of individuals with SYNGAP1-related disorder. Full article

Pathogenic variants in the MAP1B gene have been associated with neurological impairment, including intellectual disability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, brain malformations, cognitive hearing loss, short stature, and dysmorphic features. However, few cases with detailed clinical characterization have been reported. We describe a 12-year-old boy carrying a loss-of-function MAP1B variant, presenting with severe elimination disorders despite normal intelligence. He was referred to the genetics service due to persistent elimination issues, including daytime urinary incontinence, nocturnal enuresis, and fecal incontinence. He had normal motor and cognitive development, with an IQ of 99; however, he also presented with ADHD, short stature, microcephaly, and myopia. Brain MRI revealed bilaterial subependymal periventricular nodular heterotopia (PVNH). Audiometry showed normal bilateral hearing. Testing fragile X syndrome (FXS) and karyotype analyses yielded normal results. Whole exome sequencing (WES) revealed a nonsense pathogenic variant in MAP1B (c.895 C>T; p.Arg299*). No other family members showed a similar phenotype; however, a great-uncle and a great-aunt had a history of nocturnal enuresis until age 10. The patient’s deceased mother had short stature and psychiatric disorders, and a history of consanguinity was reported on the maternal side. This case broadens the phenotypic spectrum associated with MAP1B syndrome, suggesting that elimination disorder, frequently reported in FXS, should also be evaluated in MAP1B pathogenic variant carriers. In addition, the presence of short stature also appears to be part of the syndrome. Full article

Background: Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), are genetically complex and often linked to structural genomic variations such as copy number variants (CNVs). Current diagnostic strategies face challenges in interpreting the clinical significance of such variants. Methods: We developed a customized, gene-oriented chromosomal microarray (CMA) targeting 6026 genes relevant to neurodevelopment, aiming to improve diagnostic yield and candidate gene prioritization. A total of 39 patients with unexplained developmental delay, intellectual disability, and/or ASD were analyzed using this custom platform. Systems biology approaches were employed for downstream interpretation, including protein–protein interaction networks, centrality measures, and tissue-specific functional module analysis. Results: Pathogenic or likely pathogenic CNVs were identified in 31% of cases (9/29). Network analyses revealed candidate genes with key topological properties, including central “hubs” (e.g., NPEPPS, PSMG1, DOCK8) and regulatory “bottlenecks” (e.g., SLC15A4, GLT1D1, TMEM132C). Tissue- and cell-type-specific network modeling demonstrated widespread gene involvement in both prenatal and postnatal developmental modules, with glial and astrocytic networks showing notable enrichment. Several novel CNV regions with high pathogenic potential were identified and linked to neurodevelopmental phenotypes in individual patient cases. Conclusions: Customized CMA offers enhanced detection of clinically relevant CNVs and provides a framework for prioritizing novel candidate genes based on biological network integration. This approach improves diagnostic accuracy in NDDs and identifies new targets for future functional and translational studies, highlighting the importance of glial involvement and immune-related pathways in neurodevelopmental pathology. Full article

Background/Objectives: Wolf–Hirschhorn syndrome (WHS; OMIM #194190) is a rare neurodevelopmental disorder, caused by deletions in the distal short arm of chromosome 4. It is characterized by developmental delay, epilepsy, intellectual disability, and distinctive facial dysmorphism. Clinical presentation varies widely, complicating prognosis and individualized care. Methods: We assembled a cohort of 140 individuals with genetically confirmed WHS from Spain and Latin-America, and developed and validated a multidimensional, Clinician-Reported Outcome Assessment (ClinRO) based on the Global Functional Assessment of the Patient (GFAP), derived from standardized clinical questionnaires and weighted by HPO (Human Phenotype Ontology) term frequencies. The GFAP score quantitatively captures key functional domains in WHS, including neurodevelopment, epilepsy, comorbidities, and age-corrected developmental milestones (selected based on clinical experience and disease burden). Results: Higher GFAP scores are associated with worse clinical outcomes. GFAP showed strong correlations with deletion size, presence of additional genomic rearrangements, sex, and epilepsy severity. Ward’s clustering and discriminant analyses confirmed GFAP’s discriminative power, classifying over 90% of patients into clinically meaningful groups with different prognoses. Conclusions: Our findings support GFAP as a robust, WHS-specific ClinRO that may aid in stratification, prognosis, and clinical management. This tool may also serve future interventional studies as a standardized outcome measure. Beyond its clinical utility, GFAP also revealed substantial social implications. This underscores the broader socioeconomic burden of WHS and the potential value of GFAP in identifying high-support families that may benefit from targeted resources and services. Full article

Objectives: The primary objective of this study was to determine whether motor disorders are significantly more prevalent in children with Autism Spectrum Disorder (ASD) without co-occurring genetic or neurological conditions compared to neurotypical children. Another aim was to explore the applicability of the MABC-2 test for assessing motor skills in a Polish cohort of children with ASD. Additionally, this study sought to develop a basic framework for motor skill assessment in children with autism. Methods: This study included 166 Caucasian children, both sexes, aged 5–12 years, without intellectual disability (IQ ≥ 70), without concomitant genetic or neurological disorders, particularly epilepsy or cerebral palsy. The study group consisted of children with ASD (n = 71), and the control group consisted of neurotypical children (n = 95). The participants were assessed with the Movement Assessment Battery for Children–second edition (MABC-2), MABC-2 checklist and the Developmental Coordination Disorder Questionnaire (DCDQ), used as a reference point. Results: The children with ASD obtained significantly lower MABC-2 test results in all subtests in comparison with the control group. The children with suspected or diagnosed coordination disorders were characterized by a significantly greater number of co-occurring non-motor factors than the other participants of this study. MABC-2 test showed greater consistency with DCDQ than with the MABC-2 questionnaire. Conclusions: Children with ASD present a lower level of manual dexterity and balance and greater difficulties in performing tasks, including throwing and catching, in comparison with neurotypical children. The MABC-2 test with the MABC-2 checklist and DCDQ questionnaire constitute a complementary diagnostic tool. Full article

Background/Objectives: Neurodevelopmental disorders (NDDs) represent a clinically diverse group of conditions that affect brain development, often leading to varying degrees of functional impairment. Many NDDs, particularly syndromic forms, are caused by genetic mutations affecting critical cellular pathways. Ribosomopathies, a subgroup of NDDs, are linked to defects in ribosomal function, including those involving the synthesis of diphthamide, a post-translational modification of translation elongation factor 2 (eEF2). Loss-of-function (LoF) mutations in genes involved in diphthamide biosynthesis, such as DPH1, DPH2, and DPH5, result in developmental delay (DD), intellectual disability (ID), and multisystemic abnormalities. DPH5-related diphthamide deficiency syndrome has recently been reported as an ultrarare disorder linked to LoF mutations in DPH5, encoding a methyltransferase required for diphthamide synthesis. Methods: Clinical, neurological, and dysmorphological evaluations were performed by a multidisciplinary team. Brain MRI was acquired on a 3T scanner. Craniofacial abnormalities were assessed using the GestaltMatcher phenotyping tool. Whole exome sequencing (WES) was conducted on leukocyte-derived DNA with a trio-based approach. Bioinformatic analyses included variant annotation, filtering, and pathogenicity prediction using established databases and tools. Results: The affected subject carried a previously reported missense change, p.His260Arg, suggesting the occurrence of genotype–phenotype correlations and a hypomorphic behavior of the variant, likely explaining the overall milder phenotype compared to the previously reported patients with DPH5-related diphthamide deficiency syndrome. Conclusions: Overall, the co-occurrence of short stature, relative macrocephaly, congenital heart defects, variable DD/ID, minor skeletal and ectodermal features, and consistent craniofacial features suggests a differential diagnosis with Noonan syndrome and related phenotypes. Full article

Human cytomegalovirus (HCMV), a globally ubiquitous herpesvirus with the ability to carry out both lytic productive and lifelong latent infections, is a major cause of congenital infections, often leading to intellectual disabilities and neurological disorders. Moreover, HCMV is an opportunistic pathogen commonly found in immunocompromised individuals such as organ transplant recipients, HIV-positive individuals, and cancer patients, causing severe and life-threatening complications. While effective in inhibiting viral lytic infection, current FDA-approved compounds cannot eliminate the latent viral genome and have little effect on viral latent infection. Developing novel antiviral therapeutic approaches to eliminate HCMV lytic and latent infections is a major public health priority for controlling HCMV infection and preventing viral-associated diseases. The genome-editing technology based on the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein (Cas) RNA-guided nuclease system represents a novel and promising antiviral approach through modifying or destroying the genetic material of human viruses. This review summarizes the recently published progress in using the CRISPR-Cas approach to study and inhibit HCMV infections and discusses prospects for developing the CRISPR-based genome-editing technology for therapeutic applications against HCMV infection and associated diseases. Full article

This study examined the distribution characteristics of the standard scores on the Japanese version of the Cognitive Assessment System (CAS)’s Planning, Attention, Simultaneous Processing, and Successive Processing (PASS) scale by clustering the scores using the k-means method, focusing on clinical groups. In Study 1, 140 clinical cases evaluated using the CAS at University A’s educational counseling service were analyzed. The k-means clustering method was applied based on the full-scale standard scores, PASS scale scores, score discrepancies, and subtest scaled scores. Study 2 applied the same clustering method to a clinical group of 91 cases with ADHD, ASD, or comorbid ADHD–ASD, excluding those with intellectual developmental disorders or other disorders. In Study 1, a group with lower full-scale standard scores indicating general intellectual development was identified. Study 2 identified a cluster of cases with ADHD, ASD, or comorbid ADHD–ASD that showed distinct discrepancies among the four standard scores. In addition, there were no significant differences in the diagnoses across clusters. The Japanese version of the CAS provides valid cognitive profile insights in clinical settings, which can aid in planning support interventions beyond clinical diagnosis. Full article

Background/Objectives: Children and adolescents with cerebral palsy (CP) often experience associated functional limitations, diseases, or impairments. Included in these associated concerns are mental health symptoms/disorders and academic concerns. There has been an increasing research focus on the mental health of youth with CP over the past 5 years, and there is a need to synthesize this research. This review aims to synthesize the most recent research on the mental and behavioral health of youth with CP. Methods: A literature search on research focused on mental health, academic functioning, and mental and behavioral treatment for youth with CP was conducted in August of 2024 and limited to the last 5 years to highlight the most recent developments in this area of research. Four hundred and forty-eight articles were screened, and thirty-eight articles were included in this review. Results: Based on this literature review, children with CP have high rates of mental health diagnoses across multiple diagnostic areas, including autism spectrum disorder, attention-deficit hyperactivity disorder, intellectual developmental disorder, anxiety, and depression. Academic concerns are common for children with CP. Intervention studies have focused on both child and parent interventions. Conclusions: Research over the past 5 years has added to prevalence estimates of mental health disorders in the pediatric CP population. Considering the high rates of mental health symptoms found in children with CP, future research should focus further on mental health interventions for this population. Full article

Disorders of vesicular trafficking and genetic defects in autophagy play a critical role in the development of metabolic and neurometabolic diseases. These processes govern intracellular transport and lysosomal degradation, thereby maintaining cellular homeostasis. In this article, we present two siblings with a novel homozygous variant in VPS51 (Vacuolar protein sorting 51) gene (c.1511C>T; p.Thr504Met), exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. This study aimed to investigate the effects of the novel VPS51 gene variation at the RNA and protein level in fibroblasts derived from patients. A comparative proteomic analysis, which has not been previously elucidated, was performed to identify uncharacterized proteins associated with vesicular trafficking. Furthermore, the impact of disrupted pathways on mitochondria–lysosome contact sites was assessed, offering a thorough pathophysiological evaluation of GARP/EARP (Golgi Associated Retrograde Protein / Endosome Associated Retrograde Protein) complex dysfunction. An analysis of mRNA expression indicated decreased levels of the VPS51 gene, alongside modifications in the expression of autophagy-related genes (LC3B, p62, RAB7A, TBC1D15). Western blotting demonstrated a reduction in VPS51 and autophagy-related protein levels. Proteomic profiling revealed 585 differentially expressed proteins, indicating disruptions in vesicular trafficking, lysosomal function, and mitochondrial metabolism. Proteins involved in mitochondrial β-oxidation and oxidative phosphorylation exhibited downregulation, whereas pathways related to glycolysis and lipid synthesis showed upregulation. Live-cell confocal microscopy revealed a notable increase in mitochondria–lysosome contact sites in patient fibroblasts, suggesting that VPS51 protein dysfunction contributes to impaired organelle communication. The findings indicate that the novel VPS51 gene variation influences intracellular transport, autophagy, and metabolic pathways, offering new insights into its involvement in neurometabolic disorders. Full article

(1) Background: The experience of sexuality by individuals with Intellectual Development Disorder represents a significant challenge for themselves, as well as for parents, educators, and researchers. (2) Methods: Eighteen studies exploring sexual education programs aimed at individuals with ID and their caregivers were analyzed in the context of a scoping review. (3) Results: The prevention of sexual abuse, the development of healthy relationships, and the promotion of sexual autonomy are the main themes of the reviewed programs. The interventions include multimodal approaches, such as visual materials, practical activities, and role-playing, resulting in significant gains in participants’ sexual knowledge. Some limitations in conceptualization, participant recruitment, program variability, and the lack of follow-up were found. (4) Conclusions: Our study emphasizes the importance of expanding the research into sexual education for individuals with IDD and of designing programs with clearer theoretical frameworks, structure, and goals. Full article

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a rising prevalence, driven by multifactorial genetic and environmental factors. Among the genetic contributors identified, SCN2A, a critical gene encoding the Nav1.2 sodium channel, has been implicated in ASD and other related neurological conditions. This systematic review aims to explore the relationship between SCN2A mutations and ASD phenotypes. Methods: This review systematically analyzed data from studies reporting SCN2A mutations in individuals diagnosed with ASD. The primary focus was on the characterization of mutation types, associated clinical features, and phenotypic variability. Results: The mutations identified were predominantly de novo missense mutations and were associated with a spectrum of neurological and developmental challenges, including seizures, intellectual disability, movement disorders, and repetitive behaviors. A notable finding was the significant phenotypic variability observed across individuals. Gender differences emerged, suggesting a potentially greater impact on females compared to trends typically seen in ASD genetic studies. Specific mutations, such as c.2919+4delT, and mosaicism were identified as novel contributors to the observed heterogeneity. Conclusions: The review highlights the clinical significance of SCN2A mutations in ASD and highlights their relevance in genetic counseling and the development of targeted therapies. Understanding the diverse genotype–phenotype correlations associated with SCN2A can drive progress in personalized medicine, paving the way for precision therapies tailored to individuals with SCN2A-related ASD. Full article

Despite encouraging evidence for the efficacy of comprehensive and intensive behavioral intervention (CIBI) programs, the majority of studies have focused on relatively narrow, deficit-focused outcomes. More specifically, although adaptive social communication and interaction (SCI) are essential for facilitative functioning, the majority of studies have utilized instruments that capture only the severity of SCI symptoms. Thus, given the importance of the comprehensive and appropriate characterization of distinct SCI adaptive skills in CIBI, in this review, based on PubMed search strategies to identify relevant published articles, we provide a critical appraisal of two of the most commonly used adaptive functioning measures—the Vineland Adaptive Behavior Scales-Third Edition (Vineland-3) and the Adaptive Behavior Assessment System-Third Edition (ABAS-3), for characterizing SCI in the behavioral intervention context. The review focused on periodic outcome and treatment planning assessment in people with autism spectrum disorder receiving CIBI programs. Instrument technical manuals were reviewed and a PubMed search was used to identify published manuscripts, with relevance to Vineland-3 and ABAS-3 development, psychometric properties, or measure interpretation. Instrument analysis begins by introducing the roles of periodic outcome assessment for CIBI programs. Next, the Vineland-3 and ABAS-3 are evaluated in terms of their development processes, psychometric characteristics, and the practical aspects of their implementation. Examination of psychometric evidence for each measure demonstrated that the evidence for several key psychometric characteristics is either unavailable or suggests less-than-desirable properties. Evaluation of practical considerations for implementation revealed weaknesses in ongoing intervention monitoring and clinical decision support. The Vineland-3 and ABAS-3 have significant strengths for cross-sectional outpatient mental health assessment, particularly as related to the identification of intellectual disability, but also substantial weaknesses relevant to their application in CIBI outcome assessment. Alternative approaches are offered, including adopting measures specifically developed for the CIBI context. Full article

Typically developing peers are the key factor for children with disabilities to participate in inclusive settings. Good peer relationships can improve the social communication and language expression of children with disabilities, and typically developing children play a role as “gatekeepers” in the social activities of children with disabilities in the schools. In this study, 36 primary school students from grades 1 to 3 received online picture book teaching for 3 weeks, 6 units, 12 class hours, and 40 min per class hour with six volumes of disability picture books (including physical disability, deaf and hard of hearing, visual impairment, intellectual disability, learning disability and autism spectrum disorder) selected by experts in summer vocation. The attitudes of typically developing children toward peers with disabilities of participants were tested before and after attending the online picture book course. The teaching of disability-themed picture books online has significantly improved the attitudes of typically developing children in lower grades toward peers with disabilities. Specifically, there are significant differences in the sub-dimensions of emotion and positive behavior and negative behavior before and after the intervention. The results showed that online picture book teaching activities with disability themes can effectively improve the attitudes of typically developing children in primary schools toward children with disabilities in terms of cognition, emotion, and behavior, and they can be used in schools to create an inclusive climate for students with disabilities. Full article

CASK-related disorders are a form of female-restricted intellectual disabilities associated with cerebellar and pontine hypoplasia. The CASK gene is regulated by X-chromosome inactivation, which results in a mosaic distribution of CASK-expressing and CASK-deficient neurons in the female brain. This mosaic distribution is believed to play a key role in the pathophysiology of X-linked neurological disorders; however, the detailed brain structure has not been extensively characterized. In this study, we used CASK heterozygous knockout (CASK-hKO) mice combined with X-linked GFP reporter mice to investigate motor abilities and the distribution of CASK-expressing cells in the brains of female CASK-hKO mice. The CASK-hKO mice exhibited motor deficits and cerebellar hypoplasia similar to those observed in patients with CASK-related disorders. Interestingly, although half of the cerebellar granule cells were CASK-negative during early postnatal development, almost all Purkinje cells and cerebellar granule cells were CASK-positive in adulthood, suggesting that CASK expression may determine the survival of cerebellar granule cells during postnatal development. We also analyzed CASK-hypomorphic mice, which express 50% less CASK than wild-type mice, and compared hemizygous males and heterozygous females. The CASK-hypomorphic heterozygous females displayed a thinner cerebellar cortex and a higher probability of CASK-positive granule cells in CASK-hKO females, suggesting that the survival of cerebellar granule cells is regulated by a combination of cell-autonomous and cell-competitive mechanisms between CASK-expressing and CASK-deficient cells, which are generated by X-chromosome inactivation. These findings provide new insights into the relationship between the mosaic distribution of cells established by X-chromosome inactivation and the pathophysiology of CASK-related disorders. Full article